Certolizumab pegol for treating moderate to severe plaque psoriasis

3.1 Psoriasis at any level of severity can be distressing and debilitating, affecting all aspects of life (physical, psychological, social and financial), and it is a lifelong condition. The committee noted that having treatments with few or manageable side effects, and which are effective for psoriasis on the face, hands, feet and genitals, is especially important to people with psoriasis, as is having a choice of treatments.

3.2 People with plaque psoriasis may have topical therapies first line, followed by phototherapy second line. If these do not control the psoriasis, people may have systemic conventional non-biological treatments third line (such as methotrexate, ciclosporin or acitretin). If the disease does not respond to these, people may have fourth-line treatment including systemic biological treatments (such as adalimumab, brodalumab, etanercept, guselkumab, ixekizumab, infliximab, secukinumab or ustekinumab), or apremilast or dimethyl fumarate. Biosimilar versions of some biological treatments are also available. The drugs are used for as long as they continue to work. If the disease no longer responds to 1 biological treatment, people will be offered another biological treatment. This pattern is likely to be repeated over their lifetime. However, 1 clinical expert explained that switching treatments is likely to affect the effectiveness of subsequent drugs, although there is uncertainty about the degree to which this occurs. For people whose disease does not respond to multiple biological treatments, apremilast or dimethyl fumarate, the only remaining treatment option is best supportive care, which usually consists of topical agents and bandaging.

3.3 The marketing authorisation for certolizumab is for 'adults who are candidates for systemic therapy'. In its submission, the company positioned certolizumab pegol as an alternative to: systemic non-biological treatments such as methotrexate, ciclosporin and acitretin, and following topical therapy and phototherapy; or biological treatments. The committee was aware that, in previous appraisals, biological treatments were only recommended for psoriasis that has not responded to previous systemic non-biological treatments or when these treatments are contraindicated or not tolerated. The clinical experts explained that biological treatments would be unlikely to be considered at the earlier position because of their higher cost compared with the non-biological treatments used in this setting. One clinical expert stated that, if cost was not an issue, some people may prefer a biological treatment at this point in the pathway and that this approach may sometimes be reasonable. The committee agreed that certolizumab pegol is more likely to be used at the same position as alternative biological treatments, but recognised there was some interest in using it earlier. It concluded that it would consider the clinical and cost effectiveness of certolizumab pegol in both positions.

3.4 The company identified systemic non-biological treatments, such as methotrexate, ciclosporin and acitretin, as relevant comparators for people with psoriasis who had not had previous systemic treatment. The committee was aware that some other biological treatments had similar marketing authorisations to certolizumab pegol but had not been recommended for use in this population. It recalled that biological treatments are not used in this population because of their higher cost (see section 3.3). It therefore concluded that systemic non‑biological treatments were the most relevant comparators to certolizumab pegol for people who have not had systemic treatments.

3.5 The company suggested that the systemic non-biological treatments apremilast and dimethyl fumarate, used in NHS clinical practice at the same position as systemic biological treatments, were not relevant comparators for psoriasis that has not responded to previous systemic non-biological treatments, or when these treatments are contraindicated or not tolerated. The clinical expert explained that these options were rarely used in practice because they are perceived to be less effective than biological treatments. They would only be considered for use for people for whom a biological treatment was unsuitable or who were unwilling to have a biological treatment. The committee concluded that although apremilast and dimethyl fumarate are used in the NHS for some people with psoriasis, the most relevant comparators to certolizumab pegol were other biological treatments.

3.6 The main evidence for certolizumab pegol came from the CIMPASI trials 1 and 2, and the CIMPACT trial. These were double-blind randomised controlled trials that included a total of 1,020 patients with plaque psoriasis. They compared 2 doses of certolizumab pegol (200 mg or 400 mg) with placebo (all trials) and etanercept (CIMPACT only). The primary outcomes were the Psoriasis Area and Severity Index (PASI) and the static Physician Global Assessment (sPGA). They were assessed at the end of the induction period (16 weeks in the CIMPASI trials and 12 weeks in CIMPACT) as follows:

3.7 The committee considered whether patients in the CIMPASI trials and in CIMPACT were similar to those in NHS clinical practice for:

3.8 The committee noted that patients randomised to certolizumab pegol were clinically and statistically significantly more likely to have a PASI 75 and sPGA 0 or 1 response rates at week 16 compared with placebo, and a PASI 75 at week 12 compared with etanercept. The committee concluded that certolizumab pegol was more clinically effective than placebo and etanercept.

3.9 The company presented clinical evidence comparing certolizumab pegol with placebo for the subgroup of patients who had not had previous systemic treatment. This showed a statistically significant and clinically meaningful increase in response rates for certolizumab pegol compared with placebo. The clinical experts explained that the relevant comparators in people who have not had previous systemic treatment are systemic non-biological treatments (methotrexate, ciclosporin and acitretin). The committee concluded that there was no clinical trial evidence directly comparing certolizumab pegol with systemic non-biological treatments.

3.10 The company's base-case network meta-analysis compared certolizumab pegol with non-biological treatments (methotrexate, acitretin and ciclosporin). The results showed that treatment with a 200 mg maintenance dose of certolizumab pegol resulted in statistically significantly improved PASI 75 response rates compared with all the non-biological treatments. The committee noted that these results were based on a small number of patients so were highly uncertain. It concluded that a PASI 75 response was more likely with certolizumab pegol than with non-biological treatments, but the extent of this benefit was unclear.

3.11 The company's base-case network meta-analysis also compared certolizumab pegol with other biological treatments (adalimumab, brodalumab, etanercept, guselkumab, infliximab, ixekizumab, secukinumab and ustekinumab) using data from 65 trials. It showed that a 200 mg maintenance dose of certolizumab pegol resulted in PASI 75 response rates that were:

3.12 The committee noted that increasing the maintenance dose from 200 mg every 2 weeks to 400 mg every 2 weeks is within certolizumab pegol's marketing authorisation. The company stated that people whose disease had a partial response (defined as a PASI 50 to PASI 74) after 16 weeks of treatment with certolizumab pegol at a maintenance dose of 200 mg were the most likely group for whom this would be considered. It presented evidence from CIMPACT showing that most patients in this group had a PASI 75 response after a further 16 weeks of treatment with certolizumab pegol at the increased maintenance dose of 400 mg. The company stated that there were no prognostic factors identified in the trial that indicated whether a person whose disease had a partial response would be likely to have a PASI 75 response after increasing the dose. The committee noted that the trials did not compare the efficacy of increasing the dose of certolizumab pegol with either placebo or another active treatment. Also, the results for patients whose disease had a partial response were based on a small number of patients. It noted that the company's definition of partial response may have included people with a PASI 50 response and a 5‑point reduction in the DLQI, which is recommended by NICE as an alternative to the PASI 75 to assess response to treatment. The committee would have preferred to see efficacy results that excluded this group, although it recognised that this exclusion would have further reduced the number of patients whose disease was defined as having a partial response and increased the uncertainty of the clinical effectiveness of increasing the dose. The committee noted that people whose disease had a partial response to certolizumab pegol and no, or manageable, adverse events may prefer to continue on a higher dose of certolizumab pegol than to switch to an alternative treatment, which could be less well tolerated. It also noted that psoriasis is a lifelong condition and that people with psoriasis would be likely to try several treatments over their lifetime, so may wish to continue with their current treatment at a higher dose and reserve other biological treatments for future use. The committee concluded that it was appropriate to consider the cost effectiveness of increasing the dosage to 400 mg every 2 weeks in people whose disease had a partial response to certolizumab pegol 200 mg every 2 weeks.

3.13 A Markov state transition model was used to assess the cost effectiveness of certolizumab pegol. The company assumed that treatments improved quality of life but did not extend length of life. The model contained 4 health states: induction treatment, maintenance treatment, best supportive care and death. All patients entered the model in the induction state and had the first treatment in a given sequence. They moved from the induction state to the maintenance state if there was at least a PASI 75 response measured at the end of induction. From there, some patients could stop treatment for any reason and move to the next treatment in the sequence. If there was not a PASI 75 response, patients moved to the induction phase of the next treatment in the sequence. Patients moved to the best supportive care state if their psoriasis did not respond to the last active treatment in a sequence. All patients could move to the death state at any time.

3.14 The company's decision problem compared a sequence of treatments including certolizumab pegol with 8 treatment sequences excluding certolizumab pegol. The treatment sequences chosen by the company were:

3.15 The company made several assumptions in the economic model that were consistent with the approach taken in previous appraisals for psoriasis, including:

3.16 In response to clarification, the company updated its base-case analysis to incorporate several of the ERG's preferred base-case assumptions, including:

3.17 The company calculated the cost of best supportive care based on:

3.18 The lower cost of best supportive care used in the company's base case (see section 3.17) had important implications for the cost-effectiveness results from the economic model. Firstly, compared with best supportive care, no treatment in the company's model had an incremental cost-effectiveness ratio (ICER) lower than £30,000 per quality-adjusted life year (QALY) gained. Secondly, treatments with a lower efficacy could appear to be more cost effective than treatments with a higher efficacy and a similar cost. This was because treatments with lower response rates led to patients in the model advancing to best supportive care more quickly, and therefore incurring lower costs. The ERG also did an exploratory analysis incorporating assumptions from NICE's technology appraisal guidance on brodalumab, which included higher costs for best supportive care than in the company's analysis. The ERG noted that these assumptions were not necessarily superior to those in the company's base case but were presented for illustrative purposes. In this analysis, several biological treatments were cost effective compared with best supportive care. The committee concluded that it was appropriate to consider the ERG's analysis using alternative best supportive care costs in its decision making.

3.19 The committee was aware that treatment sequences, although more likely to reflect the treatment switching seen in clinical practice, may have provided misleading cost-effectiveness estimates for certolizumab pegol. It noted that some of the treatments were not cost effective in the model. Therefore, the cost effectiveness of any new treatment included early in these sequences would likely be driven by avoiding potentially cost-ineffective subsequent treatments, or by choosing treatments with lower response rates, resulting in an earlier transition to best supportive care (see section 3.18). The committee was also aware that the company's model compared a limited number of all potential treatment sequences. The ERG set subsequent options in all sequences to best supportive care, so that the only difference between sequences was the first treatment used. The committee concluded that it would consider these comparisons of individual treatments with best supportive care in its decision making.

3.20 The committee considered whether certolizumab pegol would be a cost‑effective use of NHS resources for people with severe psoriasis who have not had systemic treatment, that is, when the disease has not responded to topical treatments and phototherapy, or they are contraindicated or not tolerated (earlier than the current position for biological treatments in NHS practice). It recalled that there was no clinical evidence directly comparing certolizumab pegol with standard care in this population; evidence for the clinical efficacy of certolizumab pegol relative to methotrexate, ciclosporin and acitretin was based on the company's network meta-analysis (see section 3.10):

3.21 The committee considered whether certolizumab pegol would be a cost‑effective use of NHS resources for people with severe psoriasis for whom non-biological treatment has failed or is contraindicated or not tolerated. To do this, it took into account the patient access schemes for brodalumab, guselkumab, ixekizumab and secukinumab. The committee noted that several treatments had only small differences in total costs and QALY gains, and that these small differences could be difficult to see using ICERs from fully incremental or pairwise analyses. The ERG therefore presented the cost-effectiveness results in a net monetary benefit framework. The committee agreed that this analysis was useful to support decision making. It noted that certolizumab pegol was similarly or more cost effective than alternative biological treatments in both the company's and ERG's base cases, but recalled that these analyses may have disadvantaged treatments with higher response rates (see section 3.18). It therefore considered the ERG's alternative base case (using best supportive care costs from previous guidance) and noted that, in this analysis, compared with best supportive care, certolizumab pegol had:

3.22 The committee recalled its previous conclusion that the cost effectiveness of increasing the maintenance dose of certolizumab pegol in people whose disease partially responded should be considered (see section 3.12). It noted that the company's base case compared 2 sequences:

3.23 The company noted in its response to the appraisal consultation document that the ERG scenarios switching to alternative biological treatments (see section 3.22) used efficacy data from the CIMPACT trial for certolizumab pegol (see section 3.12) and the network meta-analysis (see section 3.11) for comparators. It was concerned that this may bias results against certolizumab pegol because this approach assumed that the comparator (used second line in the sequence) is as clinically effective as if it had been used first line. The company therefore provided additional scenario analyses which used the network meta-analysis results for both certolizumab pegol and the comparator, or (in the absence of clinical trial data for the comparator) assumed that the comparator had equivalent efficacy to certolizumab pegol in CIMPACT. The committee concluded that although this was a source of uncertainty, the scenario analyses exploring alternative assumptions had only a small effect on the cost‑effectiveness results and did not affect decision making. The company also explained that the cost of increasing the maintenance dose of certolizumab pegol may have been overestimated by a small amount because, in the model, patients who stopped certolizumab pegol 200 mg because of adverse events then had certolizumab pegol 400 mg, which would not occur in clinical practice. The committee concluded that, although this was a limitation in the model structure, the resulting overestimation in costs was likely to have a minimal effect on the cost-effectiveness results because it only applied to a small number of patients. After taking into account all confidential commercial arrangements for comparator treatments, the ICERs for certolizumab pegol were considerably above the range usually considered cost effective by NICE. The committee therefore concluded that increasing the maintenance dose was not cost effective.

3.24 Previous NICE technology appraisals for treating psoriasis have recommended stopping treatment if there is an inadequate response. An adequate response is defined as either a 75% reduction in the PASI score from when treatment started, or a 50% reduction in the PASI score and a 5‑point reduction in DLQI from when treatment started. The committee agreed that, if there was an inadequate response to certolizumab pegol, treatment should be stopped. It noted that PASI 75, assessed 16 weeks after starting treatment, was recommended as appropriate to assess response in the summary of product characteristics. It also recalled its previous conclusion that increasing the dose of certolizumab pegol when psoriasis has responded inadequately was not a cost-effective strategy (see section 3.23). The committee therefore concluded that certolizumab pegol should be stopped if there is an inadequate response at 16 weeks using the same definition of an adequate response as in previous NICE technology appraisals.

3.25 The summary of product characteristics for certolizumab pegol states that it can be used during pregnancy if clinically needed and while breastfeeding. The clinical experts considered this to be reasonable. The patient experts explained that people who are pregnant or who are considering pregnancy would welcome further effective treatment options for plaque psoriasis that do not need to be stopped before and during pregnancy (if clinically needed), or while breastfeeding. The committee concluded that these patients would value an additional treatment option.

3.26 The committee noted, as in previous NICE technology appraisals on psoriasis, potential equality issues: